This study was undertaken to examine the neural mechanisms underlying persistent inflammation and hyperalgesia. The experiments were designed to study the modulation of dorsal horn hyperexcitability and behavioral hyperalgesia by brain centrifugal systems. The dorsolateral funiculus (DLF) of the spinal cord contains descending pathways that are important for nociceptive modulation at the spinal level. To reveal the role of descending mechanisms in the development of central sensitization and hyperalgesia in response to persistent peripheral neural barrage, the effects of bilateral lesions of the dorsolateral quadrant of the spinal cord (DLFX) on inflammatory hyperalgesia were studied. Inflammation was induced by injection of complete Freund's adjuvant (CFA) or carrageenan (CARRAG) into one rat hindpaw and paw withdrawal (PW) response to a thermal stimulus was tested. Following the injection of CFA, a similar magnitude of thermal hyperalgesia developed in the injected paws of sham- operated and non-operated naive (SH, n=8), and DLFX (n=7) rats. However, when the thermal stimulus was adjusted to a lesser intensity and a low dose of CARRAG (1 mg) was injected, a significantly stronger hyperalgesia was exhibited in DLFX rats (n=6), when compared to SH rats (n=8) (ANOVA, F1,14=14.04, p<0.01). Furthermore, a contralateral hyperalgesia that is not typically seen in SH rats was unmasked within 0.5-2 h after the injection of CARRAG in DLFX rats. Compared to both groups of SH rats, the potency of morphine in inhibiting the PW response was reduced in non- inflamed DLFX rats, and further reduced in inflamed DLFX rats. The relative potencies of morphine in different groups of rats were: inflamed SH (1.00) > SH (0.62) > non-inflamed DLFX (0.16) > inflamed DLFX (0.09). These results suggest that the development of inflammatory hyperalgesia is counteracted by descending inhibitory mechanisms. Both descending inhibitory mechanisms and the suppression of spinal hyperexcitability contribute to the anti-hyperalgesic potency of morphine after inflammation. We further compared the involvement of specific brain stem sites, nucleus raphe magnus (NRM) and lateral reticular nucleus (LRN), in the modulation of spinal nociceptive neurons in CFA-inflamed rats. A local anesthetic block was produced by microinjection of lidocaine into the NRM or LRN and the changes in nociceptive neuronal activity were examined. Following the NRM lidocaine block, an increase in neuronal activity was observed in the majority of neurons, although occasionally reduced responsiveness was also seen. In contrast to the NRM lidocaine, a smaller population of dorsal horn nociceptive neurons showed an increase in activity following the LRN lidocaine block. These results suggest that the NRM and LRN may be differentially involved in plastic changes in descending pathways in the event of persistent peripheral inflammation. These studies characterize physiological and pharmacological mechanisms that contribute to the development of spinal hyperexcitability and behavioral hyperalgesia in animal models of peripheral tissue injury. A better understanding of these mechanisms may lead to improvement of the treatment of chronic pain.